Computational analysis of calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons associated with ataxia

Abstract

BackgroundMutations in the smooth endoplasmic reticulum (sER) calcium channel Inositol Trisphosphate Receptor type 1 (IP3R1) in humans with the motor function coordination disorders Spinocerebellar Ataxia Types 15 and 16 (SCA15/16) and in a corresponding mouse model, the IP3R1delta18/delta18 mice, lead to reduced IP3R1 levels. We posit that increasing IP3R1 sensitivity to IP3 in ataxias with reduced IP3R1 could restore normal calcium response. On the other hand, in mouse models of the human polyglutamine (polyQ) ataxias, SCA2, and SCA3, the primary finding appears to be hyperactive IP3R1-mediated calcium release. It has been suggested that the polyQ SCA1 mice may also show hyperactive IP3R1. Yet, SCA1 mice show downregulated gene expression of IP3R1, Homer, metabotropic glutamate receptor (mGluR), smooth endoplasmic reticulum Ca-ATP-ase (SERCA), calbindin, parvalbumin, and other calcium signaling proteins.ResultsWe create a computational model of pathological alterations in calcium signaling in cerebellar Purkinje neurons to investigate several forms of spinocerebellar ataxia associated with changes in the abundance, sensitivity, or activity of the calcium channel IP3R1. We find that increasing IP3R1 sensitivity to IP3 in computational models of SCA15/16 can restore normal calcium response if IP3R1 abundance is not too low. The studied range in IP3R1 levels reflects variability found in human and mouse ataxic models. Further, the required fold increases in sensitivity are within experimental ranges from experiments that use IP3R1 phosphorylation status to adjust its sensitivity to IP3. Results from our simulations of polyglutamine SCAs suggest that downregulation of some calcium signaling proteins may be partially compensatory. However, the downregulation of calcium buffer proteins observed in the SCA1 mice may contribute to pathology. Finally, our model suggests that the calcium-activated voltage-gated potassium channels may provide an important link between calcium metabolism and membrane potential in Purkinje cell function.ConclusionThus, we have established an initial platform for computational evaluation and prediction of ataxia pathophysiology. Specifically, the model has been used to investigate SCA15/16, SCA1, SCA2, and SCA3. Results suggest that experimental studies treating mouse models of any of these ataxias with appropriately chosen peptides resembling the C-terminal of IP3R1 could adjust receptor sensitivity, and thereby modulate calcium release and normalize IP3 response. In addition, the model supports the hypothesis of IP3R1 supersensitivity in SCA1.

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…Similar to the homozygous opt mice, the in-frame deletion of residues 1533-1538 in the middle coupling domain of D18 mutants resulted in significant reduction of IP 3 R1 expression in cerebellar PCs [54]. The D18 mutant mice may be used as a valuable mouse model for SCA15/16 [55].…”

Progressive impairment of cerebellar mGluR signalling and its therapeutic potential for cerebellar ataxia in spinocerebellar ataxia type 1 model mice

“…Inspired by the hypothesis above, it was proposed that mutant Ataxin‐1 might also cause excessive IP 3 ‐mediated dendritic Ca 2+ release from ER stores in SCA1 pathology. In addition, a recent computational study in a model of SCA1 proposed that assumed supersensitivity of IP 3 receptors could lead to upregulation of Ca 2+ signalling including mGluR‐mediated IP 3 ‐induced Ca 2+ release, regardless of reduced expression of IP 3 receptor 1, SERCA and mGluR (Brown & Loew, ). However, we think that these proposals are unlikely in SCA1 pathology, because Ataxin‐1 is localized to the PC nucleus (Skinner et al .…”

Mitochondrial impairments contribute to Spinocerebellar ataxia type 1 progression and can be ameliorated by the mitochondria-targeted antioxidant MitoQ

“…In this regard, our proteomic screen also revealed that a significant number of mitochondrial proteins involved in the ETC complexes and the ATP synthase were downregulated in mutant PCs, thereby affecting bioenergetics and proper mitochondrial functioning. Additionally, it is well accepted that calcium signaling is impaired in SCA1, SCA2 and SCA3 (Brown and Loew, 2012;Halbach et al, 2016;Kasumu et al, 2012;Pellistri et al, 2013) and as mitochondria are the second most important calcium storage organelle, improper mitochondrial functioning can negatively impact calcium homeostasis and neuronal transmission (Wang et al, 2015).…”